1. Field of the Invention
The present invention relates to methods of enhancing insulin release, enhancing GLP-1 release, increasing insulin sensitivity, increasing insulin gene expression, decreasing gastric secretion, decreasing gastric emptying, and decreasing glucagon secretion by administering to a subject an effective amount of a TRPM5 inhibitor, such as a compound according to Formula I as defined herein. The present invention also relates to methods of treating diabetes mellitus, insulin resistance syndrome, hyperglycemia, and obesity by administering to a subject an effective amount of a TRPM5 inhibitor, such as a compound according to Formula I as defined herein. This invention further relates to methods of using such TRPM5 inhibitors in the treatment of the above diseases in an animal, preferably a human or other mammal in need thereof, and to pharmaceutical compositions useful thereof. These and additional aspects of the present invention are described in further detail herein.
2. Background Art
Diabetes mellitus is a syndrome characterized by abnormal insulin production, increased urinary output and elevated blood glucose levels. There are two major subclasses which can be described based on the level of insulin production by a person's pancreatic beta cells. One is insulin-dependent diabetes mellitus (IDDM, or Type 1), formerly referred to as juvenile onset diabetes since it was evident early in life. In Type 1 Diabetes, little or no insulin is produced as the pancreatic beta cells have been destroyed by the body's own immune system. Between 5-10% of all diabetics have IDDM (American Diabetes Association. Diabetes 1996 Vital Statistics. Rockville, Md.: American Diabetes Association, 1996.) The other type is non-insulin dependent diabetes mellitus (NIDDM, or Type 2), often referred to as maturity-onset diabetes. In Type 2 Diabetes, pancreatic beta cells produce insulin but not in sufficient quantities to maintain healthy blood glucose levels. Type 2 Diabetes results from the deterioration in the molecular machinery that mediates the effectiveness of insulin function on cells (e.g., insulin resistance and inadequate insulin release). Between 90-95% of all diabetics are NIDDM (Harris, M. I., Cowie, C. C., Stem, M. P. eds. Diabetes in America, 2nd. ed. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases. NIH Publication No. 95-1468, 1995).
Type 2 diabetes is a significant healthcare problem, and its incidence is on the rise. Between 1990 and 1998, the prevalence of NIDDM in the United States increased by 33 percent, to about 13 million persons. An additional 5 million persons are presumed to have undiagnosed NIDDM, while another 14 million persons have impaired glucose tolerance. Direct medical costs associated with diabetes were $44 billion in 1997, due mainly to hyperglycemia-related diabetic complications, including diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation, and glaucoma.
Resistance to the metabolic actions of insulin is one of the key features of non-insulin dependent diabetes. Insulin resistance is characterized by impaired uptake and utilization of glucose in insulin-sensitive target organs, for example, adipocytes and skeletal muscle, and by impaired inhibition of hepatic glucose output. The functional insulin deficiency and the failure of insulin to suppress hepatic glucose output result in fasting hyperglycemia. Pancreatic beta-cells compensate for the insulin resistance by secreting increased levels of insulin. However, the beta-cells are unable to maintain this high output of insulin, and, eventually, the glucose-induced insulin release falls, leading to the deterioration of glucose homeostasis and to the subsequent development of overt diabetes.
Other metabolic disorders associated with impaired glucose utilization and insulin resistance include insulin resistance syndrome (hereinafter “IRS”), which refers to the cluster of manifestations that include insulin resistance; hyperinsulinemia; non insulin dependent diabetes mellitus (NIDDM); arterial hypertension; central (visceral) obesity; and dyslipidemia.
The primary goal of insulin resistance therapy and thus diabetes therapy is to lower blood glucose levels so as to prevent acute and long-term disease complications. For some persons, modified diet and increased exercise may be successful therapeutic options for achieving the goal of glucose control. When modified diet and increased exercise are not successful, drug therapy using oral antidiabetic agents is initiated.
Control of insulin release is very important, as there are many living diabetes patients whose pancreas is not operating correctly. In some types of diabetes, the total level of insulin is reduced below that required to maintain normal blood glucose levels. In others, the required insulin is generated but only at an unacceptable delay after the increase in blood glucose levels. In others, the body is, for some reason, resistant to the effects of insulin. If the diabetes is poorly controlled, it can lead to diabetic complications. Diabetic complications are common in Type 2 patients with approximately 50% suffering from one or more complications at the time of diagnosis (Clark, C. M., Vinicor, F. Introduction: Risks and benefits of intensive management in non-insulin-dependent diabetes mellitus. The Fifth Regensrief Conference. Ann Intern Med, 124(1, pt 2), 81-85, 1996.).
Exogenous insulin by injection is used clinically to control diabetes but suffers from several drawbacks. Insulin is a protein and thus cannot be taken orally due to digestion and degradation but must be injected. It is not always possible to attain good control of blood sugar levels by insulin administration. Insulin resistance sometimes occurs, requiring much higher doses of insulin than normal. Another shortcoming of insulin is that, while it may control hormonal abnormalities, it does not always prevent the occurrence of complications such as neuropathy, retinopathy, glomerulosclerosis, and cardiovascular disorders. Insulin regulates glucose homeostasis mainly by acting on two targets tissues: liver and muscle. Liver is the only site of glucose production, and skeletal muscle is the main site of insulin mediated glucose uptake.
There are several classes of drugs that are useful for treatment of Type 2 Diabetes: 1) insulin releasers, which directly stimulate insulin release, carrying the risk of hypoglycemia; 2) prandial insulin releasers, which potentiate glucose-induced insulin release and must be taken before each meal; 3) biguanides, including metformin, which attenuate hepatic gluconeogenesis (which is paradoxically elevated in diabetes); 4) insulin sensitizers, for example the thiazolidinedione derivatives rosiglitazone and pioglitazone, which improve peripheral responsiveness to insulin, but which have side effects like weight gain, edema, and occasional liver toxicity; and 5) insulin injections, which are often necessary in the later stages of Type 2 Diabetes when the islets have failed under chronic hyperstimulation. The effectiveness of current oral antidiabetic therapies is limited, in part, because of poor or limited glycemic control, or poor patient compliance due to unacceptable side effects. These side effects include edema weight gain, hypoglycemia, and even more serious complications.
Insulin secretagogues are standard therapy for Type 2 diabetics who have mild to moderate fasting hyperglycemia. Insulin secretors include sulfonylureas (SFUs) and the non-sulfonylureas, nateglinide and pepaglinide. The sulfonylureas are subdivided into two subcategories: the first generation agents, e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide, and the second generation agents, e.g., glyburide (glibenclamide), glipizide and gliclazide.
The insulin secretagogues have limitations that include a potential for inducing hypoglycemia, weight gain, and high primary and secondary failure rates. Approximately 10 to 20% of initially treated patients fail to show a significant treatment effect (primary failure). Secondary failure is demonstrated by an additional 20-30% loss of treatment effect after six months of treatment with insulin secretagogues. Insulin treatment is required in 50% of the insulin secretagogues responders after 5-7 years of therapy (Scheen et al., Diabetes Res. Clin. Pract. 6:533 543, 1989). Nateglinide and pepaglinide are short-acting drugs that need to be taken three times a day. They are used only for the control of post-prandial glucose and not for control of fasting glucose.
Treatment with sulfonylureas increases the risk of hypoglycemia (or insulin shock), which occurs if blood glucose levels fall below normal (UKPDS Group. UK Prospective Diabetes Study 33: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet, 352, 837-853 (1998).
Treatment with a gastrointestinal protein hormone is potentially another way to treat diabetes mellitus. Gastrointestinal protein hormones, including, but not limited to, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), stimulate insulin synthesis and secretion from the beta cells of the islets of Langerhans after food intake, thereby lowering blood glucose levels. Further, oral administration of glucose has long been known to increase insulin secretion more than intravenous glucose administration dose, despite similar plasma glucose concentration. Scow et al., Am J. Physiol., 179(3):435-438 (1954). Such an effect, called the incretin effect, provides the basis for regulating glucose disposal and treatment of diabetes and its related disease.
The most potent gastrointestinal protein hormone is GLP-1, which is initially a 37-amino acid peptide and a product of proglucagon. A subsequent endogenous cleavage between the sixth and seventh position produces the biologically active GLP-1 (7-37) peptide. GLP-1 is secreted from the L-type enteroendocrine cells in the luminal surface of the gut upon glucose intake. GLP-1 acts through a G-protein-coupled cell-surface receptor (GLP-1R) and is regulated by T1R taste receptors and gustducin. See Kokrashvili et al. AChemS XXIX Abstract, 246 (2007). Studies have shown that α-gustducin couples sweet receptor T1R3 in sugar- and sweetener-stimulated secretion of GLP-1 from the L-type enteroendocrine cells. See Jang et al. Proc. Natl. Acad. Sci. USA, 104(38): 15069-15074; Margolskee, et al., Proc. Natl. Acad. Sci. USA 104(38):15075-15080 (2007). GLP-1 possesses several physiological functions; for example, 1) it stimulates insulin synthesis from the pancreatic islet cells in a glucose-dependent manner, thereby lowering blood glucose levels; 2) it decreases glucagon secretion from the pancreas; 3) it increases beta cell mass and insulin gene expression; 4) it inhibits gastric secretion and emptying; 5) it dose-dependently inhibits food intake by increasing satiety; and 6) it promotes weight loss. Several roles for GLP-1 are described by U.S. Pat. No. 6,583,118, U.S. Pat. No. 7,211,557, U.S. Patent Appl. Pub. No. 2005/0244810, Deacon, Regulatory Peptides 128: 117-124 (2005); and Turton et al., Nature, 379, 69-72 (1996).